Psychosocial Disadvantage During Childhood and Midlife Health

Key Points Question Are childhood social hallmarks of aging (socioeconomic status and stress) associated with adult insulin resistance and epigenetic age? Findings In the National Heart, Lung, and Blood Institute Growth and Health Study, a longitudinal cohort study tracking 433 girls from 10 to 40 years of age, lower parental educational level and higher childhood perceived stress were associated with greater midlife risk (higher insulin resistance and higher epigenetic age) similarly across Black and White women. Meaning These results suggest that childhood structural and psychosocial factors are associated with aging-related health disparities.


Introduction
2][3][4][5] In adults, the social hallmarks of aging (eg, low socioeconomic status [SES] and high psychological stress) explain more variance in multimorbidity from midadulthood to late adulthood compared with traditional biological hallmarks of aging (eg, telomere attrition and genomic instability). 6Most studies have focused on adulthood and/or retrospective measures of SES or objective indicators of childhood hardship, which may contribute to higher subjective appraisals of stress but are not a direct measure of psychological stress.In this study, we leveraged the 30-year longitudinal National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) to examine independent and additive associations of low childhood SES and perceived stress in childhood with 2 well-established factors associated with mortality: insulin resistance 7,8 and epigenetic aging. 9cioeconomic disadvantage during childhood confers health risks by limiting access to educational opportunities and health care, which can translate into continued socioeconomic disadvantage and limited access to health care into adulthood. 10Individuals with low SES can also incur social stress, and a sense of lack of safety in the world can promote disease through worsened health behaviors and greater dysregulation of stress-related regulatory systems. 113][14] In a study of more than 3000 people (aged 35-45 years), lower levels of parental education were associated with worse adult metabolic functioning (ie, levels of insulin, glucose, cholesterol, and triglycerides and waist circumference). 15There are robust associations between adverse childhood experiences and insulin resistance in adulthood. 16,17However, these assessments are typically measured retrospectively and cannot capture appraisals of stress, which may be important for understanding one's susceptibility to adversity in their social environments. 18ychosocial disadvantage in childhood may promote aging-related disease risk through accelerated epigenetic aging.Second-generation epigenetic clocks (eg, GrimAge) 19 were trained on phenotypic biomarkers of aging and may represent aging pathways more proximal to social adversity. 202][23] In the Irish Longitudinal Study on Aging, 24 childhood poverty was associated with 2 additional years of epigenetic age assessed with GrimAge, which supports evidence from other studies finding childhood socioeconomic disadvantage associated with accelerated GrimAge. 25,26wever, not all studies have found a link between early-life SES and epigenetic age acceleration. 27rther, DunedinPACE, a newer pace of aging measure, was trained on a longitudinal sample of adults in midlife, making it uniquely suited for the purposes of the present study.DunedinPACE has been associated with parental and adult SES 28,29 and objective, retrospective measures of childhood stress (eg, adverse childhood experiences). 30ausible physiological pathways may help explain how early psychosocial stress contributes to cardiometabolic risk and epigenetic age.Long-term exposure to psychological stress can contribute to greater visceral fat in adults and children, [31][32][33][34] which can then decrease the effectiveness of insulin and the uptake of glucose, putting one at risk of a prediabetic state. 35Central adiposity, as measured by waist circumference, is associated with insulin resistance in childhood 36,37 and older adulthood. 38en when accounting for body mass index and body fat percentage, waist circumference remained associated with insulin sensitivity in a population of adults aged 50 to 95 years. 38In a study of 34 710 European adults, higher waist circumference was identified as a causal risk factor for accelerated epigenetic age, 39 adding to the existing literature on waist circumference and epigenetic age. 40To our knowledge, there are no existing longitudinal studies examining waist circumference as a mediator between childhood stress and accelerated biological age.
We hypothesized that lower childhood SES and higher levels of childhood perceived stress would each be associated with elevated insulin resistance, more advanced epigenetic age (GrimAge), and faster epigenetic aging (DunedinPACE) at midlife.Perceived stress may alter the observed associations between childhood SES and these outcomes.Thus, we explored whether there were independent or additive associations among SES, perceived stress, and our outcomes.We also explored whether waist circumference would mediate the associations between SES and perceived stress and the outcome variables.

Midlife Study Measures
The second-generation GrimAge epigenetic clock 19 used DNA methylation assessed in saliva sampled at 40 years of age and assayed at the UCLA Neuroscience Genomics Core (UNGC; Horvath laboratory) using a commercially available array (Infinium HumanMethulation450 BeadChip; Illumina, Inc).Grim-Age, version 2, uses age, being female, and 10 DNA methylation-based biomarkers. 19e DunedinPACE measure of pace of aging was assessed in saliva at 40 years of age by the UNGC laboratory.Values greater than 1 indicate a faster pace of aging. 44The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated from blood draws at 40 years of age assessing fasting glucose and insulin concentrations using the following standard formula: Glucose Level (in mg/dL) × Insulin Level (in μU/mL)/405 Each participant's educational level was self-reported at 40 years of age (high school or lower, some college, or college degree or higher).

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Psychosocial Disadvantage During Childhood and Midlife Health

Covariates
Race (Black and White) was both self-reported and identified by each girl's parent or guardian at baseline.Age was self-reported at the midlife point.Smoking status (current smoker or nonsmoker) was self-reported at 14 and 40 years of age.Diabetes status (yes or no) was self-reported as a diagnosis at 14 and 40 years of age.The yes category includes prediabetes.

Statistical Analysis
All data analyses were completed in R, version 4.2.2, using R Studio (R Project for Statistical Computing) from August 2, 2023, to March 18, 2024.HOMA-IR was natural log transformed before all analyses to better approximate a normal distribution.Statistical significance was defined as 2-sided P < .05.We removed 13 outliers (ie, >2 SD) for HOMA-IR (outlier range, 9.8-33.7)from the final analytic sample.Individual associations were examined before and after including plausible mediators: diabetes status, smoking status, and estimated cell type composition (for epigenetic clock analyses in line with recommendations for standardized reporting). 45,46In the remaining models, HOMA-IR models included covariates of age, diabetes status, smoking status, and race.Epigenetic clock analyses included these covariates as well as analysis cluster and estimated cell type composition to account for confounding from cell composition.Thus, GrimAge and DunedinPACE models include counts of naive CD8 + and CD4 + T cells, exhausted cytotoxic CD8 + T cells (CD8 + /CD28 -/CD45 -), natural killer cells, granulocytes, monocytes, B cells, and CD4 + and CD8 + T cells. 47r each aim, multivariable linear regression models were estimated.Hierarchical multivariable regressions were estimated along with model comparisons to determine whether adding a block significantly improved the fit of each model.We generated η p 2 effect sizes.These analyses had 3 blocks of variables based on findings in the prior step: (1) covariates only (all outcomes: diabetes status, smoking status, race; GrimAge and DunedinPACE: analysis cluster, estimated cell type compositions), (2) covariates plus SES, and (3) covariates plus SES plus childhood perceived stress.
The mediation R package was used for all exploratory mediation analyses to compute unstandardized indirect associations with 1000 bootstrapped samples. 48
The mean (SD) age at follow-up was 39.4 (1.2) years (range, 36-43 years), 135 participants (31.2%) had parents with a college degree or higher, and participants reported a mean score of 25.69 (6.68) on the Perceived Stress Scale (indicating relatively high levels of childhood perceived stress).Table 1 provides demographic characteristics and eFigure 2 in Supplement 1 provides correlations.Broadly, the results described herein do not differ across the Black and White women in our sample (eResults 1 in Supplement 1).After adjusting for midlife diabetes, smoking status, and estimated cell type composition (GrimAge and DunedinPACE only), there were no associations between childhood parental income and midlife HOMA-IR.Having a parental income of $10 000 to $19 999 was associated with higher midlife GrimAge (B = 1.33 [95% CI, 0.07-2.58];P = .04)compared with those who had a parental income of less than $10 000.There were no associations between childhood parental income and midlife DunedinPACE.
In supplemental analyses, we examined whether there were any interactions between these variables and observed limited evidence.Results are found in eTables 2 to 5 in Supplement 1.

Discussion
This longitudinal cohort study examined associations between social psychological disadvantage measured in childhood (lower SES and higher perceived stress) and age-related health in midlife (insulin resistance and epigenetic age) in a sample of Black and White women.Having parents with a lower level of education was associated with elevated insulin resistance, higher GrimAge, and faster midlife DunedinPACE; these findings remained significant even after controlling for midlife diabetes and smoking status.Higher childhood perceived stress was associated with elevated insulin resistance.Childhood perceived stress was also indirectly associated with midlife insulin resistance and GrimAge through late adolescent abdominal adiposity.These findings emphasize the importance of early childhood psychosocial disadvantage in shaping long-term health.
Having higher perceived stress as a child and a parent who had a lower level of education were uniquely and independently associated with elevated insulin resistance in midlife.This finding complements previous research showing lower parental educational levels were associated with baseline levels of childhood insulin resistance and change in insulin resistance over 3 years. 14Herein, this association persists into midadulthood.Moreover, we found a potential pathway for the associations of childhood disadvantage on adult health, such that adiposity in late adolescence mediated the association between childhood perceived stress and insulin resistance and GrimAge.
This finding highlights preliminary evidence for a lifespan perspective on psychosocial stress, adiposity, and age-related health, which would be enhanced by examining these individual factors in the context of broader structural systems (eg, schools).
When considering epigenetic age, parental educational level and parental income emerged as associated with midlife GrimAge.Exploratory analyses highlighted that parental educational level was associated with midlife GrimAge through one's own educational level, possibly reflecting intergenerational benefits of higher educational experiences.A previous study in this cohort 26 found similar results that education but not income was related to epigenetic age.Surprisingly few of the indicators of psychosocial disadvantage were associated with the pace of aging as measured by DunedinPACE, despite other studies finding that lower SES relates to faster pace of aging. 28,49ffering indicators of childhood stress, specifically measures of early-life adversity, have been associated with a faster pace of aging in midlife, but we did not find an association between childhood perceived stress and DunedinPACE.

Strengths and Limitations
There are several important strengths to this study.We followed up women over 30 years, assessing appraisals of stress and SES during childhood rather than retrospectively.These are some of the highest-quality data available to test a life course perspective on stress, adiposity, and midlife health that reflect a highly plausible mechanism (adiposity) through which early-life stress (whether structural or psychosocial) can contribute to health as one ages.
This study also has some limitations.We cannot conclude causality between childhood psychosocial disadvantage and adult health, given the longitudinal observational nature of this study, nor can we fully disentangle the associations among childhood SES, psychosocial stress, and adiposity with this design, given the complex, dynamic, and bidirectional association between stress and adiposity.The study participants were all women, and these results may not generalize to men.

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Psychosocial Disadvantage During Childhood and Midlife Health Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
a R 2 = 0.555; adjusted R 2 = 0.539.b c d A value of 1 indicates yes; a value of 0, no. e A value of 1 indicates White; a value of 2, Black.

Intergenerational Educational Experiences and Midlife Insulin Resistance and Epigenetic Age Exploratory
post hoc analyses identified that parental educational level was indirectly associated with GrimAge through one's own level of education.Findings of the post hoc analyses are provided in eResults 4 in Supplement 1.
30,50Future work should investigate these and other facets of SES to better understand area-level effects (eg, familial, neighborhood, region) for tailoring social interventions.51 KG, Kresovich JK, O'Brien KM, et al.Association of neighborhood deprivation with epigenetic aging using 4 clock metrics.JAMA Netw Open.2020;3(11):e2024329. doi:10.1001/jamanetworkopen.2020.2432952.Moffitt TE, Belsky DW, Danese A, Poulton R, Caspi A. The Longitudinal Study of Aging in Human Young Adults: knowledge gaps and research agenda.J Gerontol A Biol Sci Med Sci.2017;72(2):210-215.doi:10.1093/gerona/glw191 Comparison of Full, Analytic, and Excluded Samples eFigure 2. Correlation Matrix for Key Study Variables eResults 1. Moderation by Race eTable 2. Synergistic Analysis of Parental Educational Level and Childhood Perceived Stress in Relation to GrimAge eTable 3. Synergistic Analysis of Childhood Parental Income and Childhood Perceived Stress in Relation to GrimAge eTable 4. Synergistic Analysis of Parental Educational Level and Childhood Perceived Stress in Relation to HOMA-IR eTable 5. Synergistic Analysis of Childhood Parental Income and Childhood Perceived Stress in Relation to HOMA-IR eResults 2. Additional Mediation Results eResults 3. Sensitivity to Outlier Removal eResults 4. Intergenerational Educational Experiences and Midlife Insulin Resistance and Epigenetic Age